Acute respiratory failure is in part a manifestation of abnormal endothelial cell (EC) function. We propose to examine the alterations of pulmonary EC metabolism which may result from damage to the bronchial or pulmonary circulation. The several agents or events which will be studied include: pressure breathing with or without end expiratory pressure, toxins, lung isolation, blood and its components, hydrostatic and non hydrostatic edema, aortic clamping with tissue ischemia, sepsis and embolism. Experiments will be conducted in animals and man. Abnormalities in respiratory gas exchange will be related to EC barrier and metabolic functions. The metabolic capabilities of in-vivo lungs will be tested regarding their ability to clear and/or produce lipids, amines and peptides. Endothelial cell cultures will be used as an in-vitro model to study the consequences of exposure to varied concentrations of biogenic amines, peptides and abnormal plasma. Several newly described metabolic events of the EC will be examined both in-vivo and in-vitro: production of negative inotropic, vasoactive and vasotoxic agents; inhibition of aggregation, intrapulmonary clotting and fibrinolysis; clearance and secretion of plasminogen activator and induction of systemic proteolytic activity. Finally, the influence of the lungs on systemic hemodynamics, organ and tissue function will be explored with particular regard to the distribution of blood flow, cardiac, hepatic and renal function. It is anticipated that this program will lead to an understanding of the many normal regulating functions of pulmonary EC and the consequences of their aberant behavior.